Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

A prospective Swedish study on body size, body composition, diabetes, and prostate cancer risk

Obesity may be associated with increased risk of prostate cancer (PCa). According to one hypothesis, obesity could lower the risk of non-aggressive tumours, while simultaneously increasing the risk of aggressive cancer. Furthermore, central adiposity may be independently associated with PCa risk; it is also associated with diabetes, which itself may influence risk of PCa. We studied the associations between height, body composition, and fat distribution, diabetes prevalence and risk of total, aggressive, and non-aggressive PCa in 10 564 initially cancer-free men (aged 45–73 years) of the population-based Malmö Diet and Cancer cohort. Anthropometric and body composition measurements, including bioelectrical impedance for estimation of fat mass, were performed by study nurses. Diabetes prevalence was self-reported. Cancer cases and clinical characteristics were ascertained through national and regional registry data. Dietary and other background data were obtained through a modified diet history method and an extensive questionnaire. During a mean follow-up of 11.0 years, 817 incidental PCa cases were diagnosed. Of these, 281 were classified as aggressive. There were 202 cases occurring before 65 years of age. Height was positively associated with total and non-aggressive PCa risk. Waist–hip ratio (WHR), a measure of central adiposity, was positively associated with PCa before age 65, and less strongly, with total PCa. This association was independent of body mass index (BMI) and other potential confounders. General adiposity, expressed as BMI or body fat percentage, and prevalent diabetes were not associated with PCa risk. In this study, WHR and body height were stronger PCa predictors than general adiposity

A Potent Lead Induces Apoptosis in Pancreatic Cancer Cells

Pancreatic cancer is considered a lethal and treatment-refractory disease. To obtain a potent anticancer drug, the cytotoxic effect of 2-(benzo[d]oxazol-3(2H)-ylmethyl)- 5-((cyclohexylamino)methyl)benzene-1,4-diol, dihydrochloride (NSC48693) on human pancreatic cancer cells CFPAC-1, MiaPaCa-2, and BxPC-3 was assessed in vitro. The proliferation of CFPAC-1, MiaPaCa-2, and BxPC-3 is inhibited with IC50 value of 12.9±0.2, 20.6±0.3, and 6.2±0.6 µM at 48 h, respectively. This discovery is followed with additional analysis to demonstrate that NSC48693 inhibition is due to induction of apoptosis, including Annexin V staining, chromatins staining, and colony forming assays. It is further revealed that NSC48693 induces the release of cytochrome c, reduces mitochondrial membrane potential, generates reactive oxygen species, and activates caspase. These results collectively indicate that NSC48693 mainly induces apoptosis of CFPAC-1, MiaPaCa-2, and BxPC-3 cells by the mitochondrial-mediated apoptotic pathway. Excitingly, the study highlights an encouraging inhibition effect that human embryonic kidney (HEK-293) and liver (HL-7702) cells are more resistant to the antigrowth effect of NSC48693 compared to the three cancer cell lines. From this perspective, NSC48693 should help to open up a new opportunity for the treatment of patients with pancreatic cancer

Aspirin induces cell death and caspase-dependent phosphatidylserine externalization in HT-29 human colon adenocarcinoma cells

The induction of cell death by aspirin was analysed in HT-29 colon carcinoma cells. Aspirin induced two hallmarks of apoptosis: nuclear chromatin condensation and increase in phosphatidylserine externalization. However, aspirin did not induce either oligonucleosomal fragmentation of DNA, decrease in DNA content or nuclear fragmentation. The effect of aspirin on Annexin V binding was inhibited by the caspase inhibitor Z-VAD.fmk, indicating the involvement of caspases in the apoptotic action of aspirin. However, aspirin did not induce proteolysis of PARP, suggesting that aspirin does not increase nuclear caspase 3-like activity in HT-29 cells. This finding may be related with the ‘atypical’ features of aspirin-induced apoptosis in HT-29 cells. © 1999 Cancer Research Campaig

Psychophysiological Markers of Vulnerability to Psychopathology in Men with an Extra X Chromosome (XXY)

Studying genetically defined syndromes associated with increased risk for psychopathology may help in understanding neurodevelopmental mechanisms related to risk for psychopathology. Klinefelter syndrome (47,XXY) is one of the most common sex chromosomal aneuploidies (1 in 650 male births) and associated with increased vulnerability for psychopathology, including psychotic symptoms. Yet, it remains unknown whether this increased risk is associated with underlying psychophysiological mechanisms that are typically deficient in individuals with psychotic disorders. The present study assessed three “classic” psychophysiological markers of psychosis in Klinefelter syndrome (KS): smooth pursuit eye movements (SPEM), prepulse inhibition (PPI) and P50 suppression. Fourteen adults with KS and 15 non-clinical adults participated in the study. Data on SPEM (reflecting visuo-motor control) as well as PPI and P50 suppression (reflecting sensory gating) were collected. Dysfunctions in SPEM were observed in individuals with KS, with less smooth pursuit as expressed in lower position gain. Also, reduced sensory gating in individuals with KS was suggested by significantly reduced prepulse inhibition of the startle response (PPI) (effect size 1.6). No abnormalities were found in suppression of the P50 (effect size 0.6). We speculate that impairments in these psychophysiological mechanisms may reflect core brain dysfunctions that may also mediate the described increased vulnerability for psychotic symptoms in KS. Although speculative, such deficit specific, rather than disorder specific, psychophysiological dysfunctions in KS might convey vulnerability to other types of psychopathology as well. As KS already can be diagnosed prenatally, the predictive value of childhood impairments in prepulse inhibition and smooth pursuit for development of psychopathology later in life could be assessed. In sum, studying individuals with KS may prove to be an avenue of research leading to new hypotheses and insights into “at risk” pathways to psychopathology

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment

Background High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods We used data for exposure to risk factors by country, age group, and sex from pooled analyses of populationbased health surveys. We obtained relative risks for the eff ects of risk factors on cause-specifi c mortality from metaanalyses of large prospective studies. We calculated the population attributable fractions for- each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the eff ects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specifi c population attributable fractions by the number of disease-specifi c deaths. We obtained cause-specifi c mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the fi nal estimates. Findings In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10\ub78 million deaths, 95% CI 10\ub71\u201311\ub75) of deaths from these diseases in 2010 were attributable to the combined eff ect of these four metabolic risk factors, compared with 67% (7\ub71 million deaths, 6\ub76\u20137\ub76) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined eff ects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing eff ect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the globalresponse to non-communicable diseases